Liver Disease in Women: Evaluation of Abnormal Liver Tests None - - PDF document

Liver Disease in Women:

Evaluation of Abnormal Liver Tests

UCSF Controversies in Women’s Health Symposium

Monika Sarkar, MD, MAS UCSF Division of GI/Hepatology December 9th, 2016

Disclosures

• None

Outline:

• Outpatient evaluation
• The key players
• Why sex matters
• Primary care management

Approach to Women with Abnormal LFTS (Liver Function Tests)

Which are tests of liver FUNCTION?

• Total bilirubin
• Albumin
• Prothrombin time/INR

But not:

• AST/ALT/Alkaline phosphatase

Approach to Women with Abnormal Liver Function Tests

What is “normal”?

• Normal = mean of

the distribution ± 2 SD

• f the “normal” population
• 5% of “normal” patients

will have values outside of the normal range

• 2.5% above and 2.5% below
• Normal ALT varies by sex:
• ULN of ALT = 19U/L in women & 30 in men1
• Lower threshold than flagged by most labs!
• 1. Prati et al, Annals of Internal Med, 2002

Two general patterns of liver injury

• Hepatocellular: Predominately AST and ALT
• Cholestatic: Predominately Tbili and alk phos

Degree of Elevation Common Causes Mild (<100 U/L) Chronic viral hepatitis, alcohol, NAFLD, drug induced, hemochromatosis, autoimmune Moderate (100-300 U/L) As above Severe (>1000 U/L) Drug induced (ie acetominophen, antibiotics) Acute viral hepatitis Autoimmune hepatitis Ischemia/Hypoperfusion Degree of Alk Phos Elevation Common Causes Low (less than normal) Wilson’s Disease Mild elevation Biliary obstruction (ie stones) Moderate elevation Primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) Severe (>1000 IU/L) Malignant infiltration by tumor

Case

• 60 yo woman presents for new primary

care evaluation

• Routine labs: Tbili 0.8, AST 120, ALT

90, AP 111 (ULN 95)

• One year ago: Tbili 0.6, AST 97, ALT

83, AP 120

Case- history

PMH: Hypertension, dyslipidemia, hypothyroidism, chronic back pain, recurrent UTIs Menopausal history: Menopause at age 46 yo

Meds: HCTZ, pravastin, tylenol 2-3g 1-2x per week, macrobid, levothyroxine

SHx: Has one glass of wine per night, no tobacco use, IVDU x 1 in 1973 FH M th ith t 2 di b t

Physical Exam

VS: T 37.3 HR 72 BP 149/79 SaO2 99% RA, BMI 35 General: overweight, interactive CV: Normal Respiratory: Normal Abdominal: soft, central adiposity, non tender, no hepatosplenomegaly Extremities: warm, no edema Skin- no palmar erythema, no spider angiomata, no acanthosis

39.0 5.3 185 137 151 3.8 0.8 120 111 90 0.8 1.0

Initial Labs

Albumin 3.8

8

HgAIC 6.3 Lipids: TG 161, HDL 40, LDL 101

Case- Moderate Hepatocellular Injury

(Tbili 0.8, AST 120, ALT 90, Alk phos 111)

What additional testing would you perform? Risk for Hepatitis C?

PMH: Hypertension, hyperlipidemia, hypothyroidism, chronic back pain, recurrent UTIs Menopausal history: Menopause at age 46 yo Meds: HCTZ, pravastin, tylenol 2-3g 1-2x per week, macrobid, levothyroxine SHx: Has one glass of wine per night, no tobacco use, IVDU x 1 in 1973 FHx: Mother with type 2 diabetes ID: 60 yo woman, born in 1956

Baby Boomers

• Risk assessment misses

50% of infected patients

• Screen with HCV Ab
• Birth cohort testing

is cost effective

Majajan, Am J Public Health 2013; MMWR Recomm Rep. 2012

Does menopausal age matter in Hepatitis C?

• Liver cells incubated in estrogen make less

collagen- anti-fibrotic role of estrogens1 Cross sectional data show:

• More severe liver fibrosis in post compared to

pre-menopausal women2,3

• HRT protects against hepatic fibrosis2,3
• Fibrosis progression more rapid in nulliparous

women3

1.Itagaki, Gut 2005, 2. Codes et al Gut 2007, 3.Di Martino, Hepatology 2004

Accelerated HCV Fibrosis Begins in Peri-menopausal Years

• n=405 HIV/HCV co-infected

women, followed for 18 yrs

• Anti-mullerian hormone

(AMH) measured every 6 months

• Assessed rate of fibrosis in

each women

• Captured peri-menopause

(within 5 years of AMH loss) and menopause

• Fibrosis starts to accelerate

in peri-menopausal years

Sarkar et al, AASLD November 11, 2015

Why Cure HCV?

• High chance of cure (95-

100%), tolerable side effects, short course

• Halt progression, cause

regression of fibrosis

• Reduced risk of

cirrhosis, liver cancer, and LT

• Decreased all cause

mortality

• For early stage disease, 15 year

survival higher in patients cured

• f HCV (93% vs 82%, p=0.003)
• Cost of therapy declining as

more meds flood the market & shorter durations

• Decreased transmission in IDU
• Extrahepatic manifestations

improve: cognitive function, quality of life, work productivity, insulin sensitivity

AASLD-IDSA, 2016; Morgan, Hepatology 2010; Bennett, Eur J Health Econ. 2016, Jezequel C, EASL 2016; Hellard M, Hepatology 2014; Gerber, Clin Gastroenterol Hepatol. 2016; Hsu, Hepatology. 2014

Who Should Be Referred for HCV Treatment?

anyone AASLD-IDSA, February 2016

Our patient is HCV Ab negative!

Could This Be Medication Related?

60 yo woman PMH: Hypertension, hyperlipidemia, hypothyroidism, chronic back pain, recurrent UTIs Menopausal history: Menopause at age 46 yo Meds: HCTZ, pravastin 10 yrs, tylenol 3g per day 1-2 times per week, macrobid x 3 months SHx: Has one glass of wine per night, no tobacco use, IVDU x 1 in 1973 FHx: Mother with type 2 diabetes

Sex Differences in Drug- Induced Liver Injury

• Women more likely to have drug induced

liver injury from a spectrum of agents1,2

• Women account for ~ 70% of cases of

drug induced acute liver failure (ALF)2,3

1.Navarro, NEJM 2006, 2.Reuben et al, Hepatology 2010, 3.Sarkar et al, AASLD November 11th, 2016

Acetaminophen (APAP/tylenol) toxicity

• Most common cause of acute liver failure
• So why do hepatologists love tylenol for

pain control? ≤ 3g per day is safe for healthy livers ≤ 2g per day is safe for cirrhotic livers

• Among 145 healthy adults taking 4 grams of APAP per

day (RCT of different pain regimens):

• 76% had at least one ALT > 40
• 53% had peak ALT > 80
• 39% had peak ALT > 120
• Similar risk by sex

Watkins, JAMA 2006; livertox.nlm.nih.gov

Macrobid started 3 months ago, not the likely culprit…

Statin Hepatotoxicity

• Mild elevations present- 3-15% of patients
• Higher elevations (ALT > 3xULN) in < 1%
• Dose dependent but typically self limited

without dose reduction

• Clinically significant injury extremely rare
• Discontinue if ALT > 10xULN (ie ALT >

200 in women)

livertox.nlm.nih.gov

Might be statin related, but let’s rule out other causes

• HIV Ab - Recommended by CDC for all patients 13-64 yo
• Hepatitis B: HBsAg -, HBcAb IgG -, HBsAb -

HBsAg: tests for chronic infection HBcAb IgG: tests for exposure to virus (past or current) HBcIgM: tests for acute hepatitis B HBsAb: tests for immunity to hepatitis B (cleared or vaccinated) HBeAg/eAb: characterizes chronic HBV

• Hepatitis A: HAV Ab IgG+

HAV Ab IgG: to assess immunity HAV Ab IgM: tests for acute hep A (AST/ALT 1000s, N/V/jaundice)

Additional Viral Testing

Additional testing

• Abdominal US with dopplers
• smooth contour
• normal spleen
• patent hepatic vessels
• hepatic steatosis
• Iron level 54, Tsat 21%, Ferritin 105

Could This Be Hereditary Hemochromatosis (HHC)?

• Most common genetic disorder among Caucasians
• Prevalence: 1:250 individuals of Northern European

descent

• Mutation in genes involved in iron regulation
• AASLD guidelines: suspect HHC in patients with

transferrin saturation >45% AND elevated ferritin (>200 ug/L for women, >300 ug/L for men)

• Diagnose by HFE genotype (not needed in our patient)
• Elevated ferritin present in >20% of pts with

nonalcoholic steatohepatitis (NASH)

Bacon, Hepatology 2011; Knowdley, Hepatology 2012

Additional testing

• Abdominal US with dopplers: smooth

contour, normal spleen, patent hepatic vessels, hepatic steatosis

• Iron level 54, Tsat 21%, Ferritin 105
• Autoimmune markers: ANA + 1:40, ASMA

+ 1:80, IgG 1200 (normal)

Risk for Autoimmune Disease?

60 yo woman PMH: Hypertension, hyperlipidemia, hypothyroidism, chronic back pain, recurrent UTIs Meds: HCTZ, pravastin, tylenol PRN, macrobid, levothyroxine SHx: Has one glass of wine per night, no tobacco use, IVDU x 1 in 1973 FHx: Mother with type 2 diabetes

Autoimmune Liver Disease

Autoimmune Hepatitis

• F:M = 4:1
• All ages
• Prevalence: ~ 15/100,000
• Hepatocellular pattern

Diagnosis:

• Serologies: ANA, ASMA,

and IgG level

• Liver biopsy
• No need for anti-LKM

Primary Biliary Cholangitis (PBC)

• F:M = 9:1
• Mean age 50s
• Prevalence: 40/100,000
• Cholestatic pattern

Diagnosis:

• Elevated alk phos & AMA
• Liver biopsy not required
• ~ 5% of PBC pts are AMA neg

Manns, et al, Hepatology 2010, Kaplan/Gershwin, NEJM 2005

Question

What is most likely cause of abnormal liver tests? 1) Autoimmune hepatitis 2) Autoimmune hepatitis plus NAFLD 3) Nonalcoholic Fatty Liver Disease (NAFLD)

Question

What is most likely cause of abnormal liver tests? 1) Autoimmune hepatitis 2) Autoimmune hepatitis plus NAFLD 3) Nonalcoholic Fatty Liver Disease (NAFLD)

Autoantibodies in NAFLD

• Positive ANA > 1:160 or ASMA >1:40 present

in ~ ¼ of patients with NAFLD

• Positive AMA ~ 8% patients with NAFLD
• Autoimmune markers are not associated with

severity of NASH on liver biopsy

Vuppalanchi R et al., Hepatol Int 2011

Risk for Fatty Liver Disease?

PMH: Hypertension, dyslipidemia, hypothyroidism, chronic back pain, recurrent UTIs Menopausal history: Menopause at age 46 yo Meds: HCTZ, pravastin, tylenol PRN, macrobid SHx: Has one glass of wine per night?, no tobacco use, IVDU x 1 in 1973 FHx: Mother with type 2 diabetes Physical Exam: BMI 35

Drugs and Toxins – ALCOHOL – Corticosteroids – Tamoxifen – Amiodarone – Industrial solvents

Causes of Fatty Liver

Nutritional Syndromes – JI Bypass – TPN – Rapid weight loss Inherited Metabolic Diseases – Lipodystrophy – Abetalipoprotinemia – Wilson’s Disease Drugs and Toxins – Alcohol – Corticosteroids – Tamoxifen – Amiodarone – Industrial solvents Metabolic Syndrome – IR/DM – Obesity – Dyslipidemia – Hypertension Nutritional Syndromes – Small bowel bypass – TPN – Rapid weight loss Inherited Metabolic Diseases – Lipodystrophy – Abetalipoprotinemia – Wilson’s Disease

Causes of Fatty Liver

Obesity Trends Among U.S. Adults

1990

BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person No Data <10% 10%–14%

Obesity Trends Among U.S. Adults

2000

No Data <10% 10%–14% 15%–19% ≥20%

Obesity Trends Among U.S. Adults

2010

No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%

Epidemiology

• What is the prevalence of NAFLD in general

population? 30%- It is the #1 most common cause of chronic liver disease in the United States

• Prevalence of NAFLD in hyperlipidemia?

50%

• Prevalence of NAFLD in DM2?

70%

• Prevalence of NAFLD in morbid obesity?

80-90%

NAFLD = Hepatic Manifestation of the Metabolic Syndrome

Chalasani et al., Am J Gastro 2012

Fat

Fat +Inflammation ± Fibrosis Cirrhosis ± Inflammation ± Fat

Simple steatosis NASH: Non alcoholic

steatohepatitis

NAFLD: Non Alcoholic Fatty Liver Disease

NAFLD 30% NASH F>M ~ 15 million U.S. women

NASH Cirrhosis Cirrhosis Related Complications…

20% 40-60% over 5-7 yrs

Natural History

Rinella ME, JAMA 2015

5-15%

Public Health Implications

NASH will be leading cause of: Cirrhosis

Charlton et al., Gastro 2011; Wong et al Hepatology 2014

Hepatocellular Carcinoma Liver Transplant

….in less than 5 years

Does Menopause Matter in NAFLD?

• Similar to other metabolic co-morbidities, risk
• f NAFLD increases after menopause.
• HRT is associated with lower risk of NAFLD

in post-menopausal women.1

• Severity of NASH fibrosis is greater in:

1) post- vs pre-menopausal women2,3 2) women with earlier age at menopause3

1.Clark/Diel, Gastro 2002; 2.Yang, Hepatology 2014; 3.Klair et al, Hepatology 2016

1) What is the most common cause of death in patients with NAFLD?

• 1. Cirrhosis with portal hypertensive

complications

• 2. Hepatocellular carcinoma (HCC)
• 3. Cardiovascular disease

1) What is the most common cause of death in patients with NAFLD?

• 1. Cirrhosis with portal hypertensive

complications

• 2. Hepatocellular carcinoma (HCC)
• 3. Cardiovascular disease

Mortality in NAFLD

• NHANES III

(1988-2000)

• Eligible: 12,822

(817 NAFLD)

• F/U: 8.7 yrs

(median)

HR= 9.32 (9.21-9.43) HR= 1.038 (1.036-1.041) Ong et al. J Hepatology 2008

Causes of death in NAFLD: 1) CV 2) Malignancy 3) Liver

Independent Risk Factors for Clinically Significant CAD

Variable OR 95% CI P Value

Fatty Liver 8.48 4.39‐16.40 <0.001 Diabetes 2.54 1.47‐5.91 0.002 Male Sex 2.31 1.19‐4.48 0.014 HTN 1.63 0.90‐2.98 0.106 LDL 0.99 0.99‐1.00 0.201

Mirbagheri et al. Liver Internat. 2007

• n=317 elective coronary angiogram
• n=85 normal or mild CAD and n=232 clinically

relevant CAD

Additional High Risk Groups

• Hypothyroidism
• Obstructive Sleep Apnea
• Hypopituitarism & Hypogonadism
• Polycystic Ovary Syndrome

AASLD Practice Guidelines NAFLD 2014

PCOS Diagnostic Criteria

Hyperandrogenism Oligomenorrhea

Rotterdam Criteria (2/3):

1) Oligomenorrhea 2) Increased ovarian follicles # 3) Hyperandrogenism

Polycystic Ovaries

Prevalence: ~10% of pre-menopausal women!

Teede et al, BMC 2010; Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group, 2004.

Epidemiology: NAFLD in PCOS

• ~50% of PCOS women have ultrasound

evidence of NAFLD1-4

• At least 1/3 have elevated liver tests4-6

~ 60% with ALT > 19U/L5

• Likely relates to overlapping metabolic

risk factors…

• 1. Gambarin-Gelwan et al, Clin Gastro Hep 2007; 2. Ma et al, J Clin Endocrinol Metabol 2011;
• 3. Cussons et al, J Clin Endocrinol Metabol 2009; 4. Cerda et al, J Hepatology 2007;
• 5. Gangale et al, Clin Endocrinol 2011; 6. Schwimmer et al, Fertility and Sterilty 2005

Metabolic Co-Morbidities in PCOS

• 65-70% have insulin resistance
• 50% have metabolic syndrome: 7x higher

than age matched non PCOS controls

• Glucose intolerance or DM2 develops by

age 30 years in 30-50% of obese women

Moran et al, Human Reprod 2010; Vassilatou E, WJG 2014

PCOS Phenotypes Are Variable- May be Subtle

10 20 30 40 50 60 70 80 90 Lean Lean PCOS Obese Obese PCOS Insulin Resistance (min -1/nmol/ml)

Adapted from Dunaif A, et al. JCEM, 1996

Thin Women With PCOS Also Develop IR PCOS in NAFLD

• n=71 pre-menopausal women with NAFLD: 43%

diagnosed with PCOS1

• Pre-menopausal women with NAFLD attending a

liver clinic (n=14)2

• 71% diagnosed with PCOS
• n=5 biopsied- all had steatohepatitis
• It is worth inquiring about menstrual cycles and

hirsutism in your pre-menopausal patients with NAFLD

1.Vassilatou et al, Eur J Endocrinol. 2015; 2.Brzozowska et al, J Gastro Hep 2009

Testosterone Level in Pre-Menopausal Women Is Associated With Prevalent NAFLD 25 Years Later (n=1052)

Sarkar et al, AASLD presentation, November 12th, 2016

Exclude other causes of liver disease Abdominal imaging with steatosis +/‐ elevated liver enzymes

Back to our patient…Diagnosing NAFLD

What To Order in Primary Care Setting

HIV Ab HAV IgG HBV sAg / sAb / cAb IgG HCV Ab For hemochromatosis: Iron level, Tsat, ferritin US with dopplers: assess for vessel patency, steatosis, cirrhosis, portal HTN Reasonable in women (but can defer to hepatology): For autoimmune hepatitis: ANA, ASMA, and IgG level For primary biliary cholangitis: AMA

Referred to Hepatology

• Could alcohol look

like this? Yes

• Doesn’t AST>ALT

indicate alcohol? (AST 120/ALT 90) It might.

• AST: ALT > 2 is

classic for alcoholic steatohepatitis

• Lots of fat
• Grade 2/3 inflammation
• Stage 3/4 scarring

Alcoholic Liver Disease (ALD) in Women

• Women at higher risk for ALD than men: higher blood alcohol

levels with same amount of alcohol intake

• Women are smaller, less total body water, & decreased

gastric alcohol dehydrogenase

• Max recommended drinks per week: 7 in women vs 14 in

men

Barrio E,et al , Alcohol Clin Exp Res 2004, Sato et al, Alcohol Clin Exp Res 2001, Baraona et al, Alcohol Clin Exp Res 2001, Frezza et al, N Engl J Med 1990; Lelbach et al, Alcoholic Liver Pathology, 1975

Standard drink ~12-14 g

Referred to Hepatology

• AST > ALT also

suggests advanced scarring in NASH.

• Lots of fat
• Grade 2/3 inflammation
• Stage 3/4 scarring

NAFLD TREATMENT

Exercise

Moderate intensity aerobic activity 3‐6 times per week for 1‐3 months no weight change but:

• Improved AST/ALT
• Decreases hepatic fat on imaging
• No data on histologic benefits
• Long term maintenance difficult

Thoma C et al., J Hepatol 2012

Nutrition

• Ideal NAFLD diet not clear: Mediterranean, Paleo?
• Saturated fat and fructose stimulate hepatic lipid

deposition

• Low‐mod fat restriction with mod‐high carb restriction

for 1‐6 months 4‐14% decreased weight

• Improved AST/ALT, insulin resistance, and hepatic fat

Thoma C et al., J Hepatol 2012

The Whole Package: Diet, Exercise, Behavioral Modification

• 31 obese pts, randomized 2:1 in Lifestyle (LS) vs

Structured Education (controls) for 48 wks

• LS lost 9.3% versus 0.2% in controls, p= 0.003
• More histologic improvement in LS group (72% vs 30%,

p=0.03)

• Weight loss of ≥7% associated with improved

inflammation and scarring (p <0.05)

Pomrat et al., Hepatology 2010

MEDICATIONS FOR NASH

• RTC: Adults with biopsy proven NASH
• Excluded DM and cirrhosis
• Randomized to pioglitazone (n=80), Vitamin E (n=84),
• r placebo (n=83) for 2 years
• 1°endpoint = Improved liver histology

Sanyal et al, NEJM 2010

PIVENS Trial: Pioglitzazone,

Vitamin E, or Placebo for Non Alcoholic Steatohepatitis

PIVENS

Histologic Improvement in NASH

5 10 15 20 25 30 35 40 45 50 Vit E Placebo Pioglitazone % Improved

P = 0.001 P = 0.04 43% 34% 19%

Sanyal et al, NEJM 2010

Pioglitazone in NASH

• Side effect profile may limit use:
• CV events, CHF, weight gain 3-5kg in 70% pts,

bladder cancer?, bone fractures in post menopausal women

• Longterm safety and efficacy in NASH unknown

Aliment Pharmacol Ther. 2012

Our Patient

• Started Vitamin E 800 IU/day.
• Joined gym and lost 10 pounds in 6 months.
• Repeat liver tests at one year:
• AST 120  45
• ALT 90  50
• Remains at risk for heart disease and

progressive fibrosis…aggressive co- management by PCP and hepatology is key!

Summary (I)

• ALT: most sensitive marker of liver injury,

ALT > 19U/L is abnormal in women

• PCP w/u: alcohol/medication history, viral

serologies, iron studies, and abdominal US

• Hepatotoxicity is more common in women:

NIH LiverTox website is great resource!

• Screen baby boomers with HCV Ab
• Consider HCV treatment in patients without

life-threatening comorbidities

• NAFLD is most common chronic liver disease,

present in 1/3 Americans

• NASH is more common in women
• NASH and HCV fibrosis accelerate after

menopause

Summary (II)

• CAD is #1 cause of death in NAFLD
• Women with PCOS have high risk for NAFLD
• Consider screening PCOS women for NAFLD
• Inquire about menstrual cycles and hirsutism

in pre-menopausal women with NAFLD

• Resource permitting, consider hepatology

evaluation for all patients with NAFLD

Summary (III)

Thank you!

• Questions….

Happy Holidays!

monika.sarkar@ucsf.edu